Project Descripfion: This proposal seeks to develop a novel, cardiac specific and ulfimately translatable therapy for diastolic heart failure (DHF) based on the cardiac specific over-expression of the natriuretic pepfide receptor (guanylyl cyclase A (GCA)) via adeno-associated viral (AAV) gene delivery. We will optimize overexpression of GCA in rodent heart, demonstrate that restoration of cardiac GCA via gene delivery prevents heart failure in GCA deficient mice (mice with systemic (GCAnull) and mice with cardiac specific (CS- GCAnull) ablation of the GCA gene) and reverses heart failure in wild type mice with established DHF. These studies lay the foundation for translation to large mammal and human DHF in future studies.